Clinical relevance of decreased free protein S levels: results from a retrospective family cohort study involving 1143 relatives

Abstract

Conflicting data have been reported on the risk for venous thrombosis in subjects with low free protein S levels. We performed a post-hoc analysis in a singlecenter retrospective thrombophilic family cohort, to define the optimal free protein S level that can identify subjects at risk for venous thrombosis. Relatives (1143) were analyzed. Relatives with venous thrombosis (mean age 39 years) had lower free protein S levels than relatives without venous thrombosis (P < .001), which was most pronounced in the lowest quartile. Only relatives with free protein S levels less than the 5th percentile (< 41 IU/dL) or less than the 2.5th percentile (< 33 IU/dL) were at higher risk of first venous thrombosis compared with the upper quartile (> 91 IU/dL); annual incidence 1.20% (95% confidence interval [CI], 0.72-1.87) and 1.81% (95% CI, 1.01-2.99), respectively; adjusted hazard ratios 5.6, (95% CI, 2.7-11.5) and 11.3 (95% CI , IntroductionProtein S is a vitamin K-dependent plasma glycoprotein that functions as a nonenzymatic cofactor of activated protein C in the inactivation of the procoagulant factors Va and VIIIa, and plays an important role in regulating thrombin generation. 1 Approximately 60% of total protein S is bound to complement component C4b-binding protein. 2 Until recently, it was believed that only free protein S has activated protein C cofactor activity. However, new evidence suggests that both bound and free protein S are cofactors for activated protein C. 3 Three subtypes of protein S deficiency are recognized: type I, with decreased levels of both total and free protein S antigen (ie, a quantitative defect); type II, with total and free protein S antigen levels within their normal ranges, but decreased protein S activity (ie, a qualitative defect); and type III, with decreased free protein S and normal total protein S antigen levels. 4 Whereas type I deficiency is an established risk factor for venous thrombosis, 5,6 conflicting data have been reported on the risk of thrombosis associated with type III deficiency. [6][7][8][9][10][11][12][13][14] A difference in risk between subjects with type I and type III deficiency, together with variation in the studied populations may explain this discrepancy. Another explanation could be that the cutoff level for protein S deficiency type III (ie, the lower limit of the normal range; in our laboratory Ͻ 65 IU/dL) is too high to identify subjects at risk for venous thrombosis. 11 Moreover, studies that did not show an increased risk of venous thrombosis in association with free protein S deficiency may have been confounded by the inclusion of subjects with mild decrements in free protein S levels. The diagnostic criteria for type III protein S deficiency therefore likely need to be reconsidered.We performed a retrospective study in a large series of families to assess the absolute risk of first venous thrombosis and its recurrence for different free protein S levels, to define an optimal cutoff level of free protein S to identify subjects at risk for venous thrombo...

Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives

“…Protein S type III deficiency was separately analyzed in a previous article of ours, where it showed to be an independent risk factor for venous thrombosis when free protein S levels were much lower than the lower limit of the normal range. 18 Protein C deficiency type I and type II were defined by decreased levels or activity of protein C antigen (both Ͻ 65 IU/dL). Deficiencies were considered inherited if they were confirmed by measuring a second sample that was collected 3 months later and were found in at least 2 family members.…”

C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S–independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies

“…12 Such complex and elusive mechanisms could explain why, despite the key role of PS in the regulation of thrombin generation, its involvement in the susceptibility of venous thrombosis (VT) remains obscure. Although PS deficiency is considered a risk factor for VT, [13][14][15] total PS and fPS show very little correlation with VT. 16,17 C4BP is a large plasma protein existing in 3 different isoforms, ␣ 7 ␤ 1 , ␣ 7 ␤ 0 , and ␣ 6 ␤ 1 , according to the number of identical ␣-chains (6 or 7) and the presence/absence of a single ␤-chain. 18 The main isoform is ␣ 7 ␤ 1 , whereas the ␣ 7 ␤ 0 isoform lacking the ␤-chain represents approximately 17% of the C4BP molecules.…”

Molecular basis of protein S deficiency in China

“…The prevalence of heterozygous ProS deficiency is 2-8% in thrombosis patients in Caucasian populations [15], whereas the prevalence in the general population is estimated to be 0.03-0.13% in Caucasians and 0.06-1.12% in Southeast Asians [16][17][18]. Familial and case-control studies suggest that PSD is associated with a 2.5-to 11-fold increased risk of venous thrombosis [15,19,20]. In addition to congenital deficiency, there are a number of physiologic and pathologic conditions that lead to decreased plasma ProS levels such as oral contraceptives, pregnancy, hormone-replacement therapy, and hepatic disorders [21,22].…”

“…However, some reports have suggested that Type I and Type III are actually two phenotypes of the same genetic defect [23,24]. In addition, several studies suggest that the partial effect of missense mutations could correlate well with the phenotype of ProS deficiency [15,20,[25][26][27]. Plasma protein S parameters (activity and free ProS level) depend on the nature of the missense mutations and the secretion differences.…”